PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is especially deadly due to the lack of early detection and effective therapies. The unique plasticity of differentiation states of PDA, starting at tumor formation and continuing throughout tumor progression and metastasis, may be partially responsible for the recalcitrance of PDA to current therapies. Exposing the true identity of the normal cell origin(s) of PDA may help us characterize differentiation pathways run awry in the pancreatic oncogenesis and teach us how to approach the disease. By interrogating the earliest steps of tumor formation, we may learn to design new therapies to constrain or even reverse the aberrant differentiation that is an intrinsic part of the devastating PDA. In this application we will focus on pancreatic intraductal papillary mucinous neoplasms (IPMNs), one of the three precancerous lesions of PDA. Patients with PDA derived from IPMN often face better prognosis than those derived from PanIN (Pancreatic intraepithelial neoplasias), and the underlying reason for the differential prognosis is not understood. In this application we will in Aim 1: determine the cell of origin of IPMN and genes/pathways that may regulate the dichotomy of PanIN and IPMN development. In Aim 2: investigate if DCLK1+ cells share the same cell of origin as IPMN tumor cells and if they are potential therapeutic targets. One major challenge in caring for IPMN patients is to identify those who would benefit from surgical intervention. Despite the Sendai guidelines, the management of branch BD-IPMN under the guidelines regarding surgery or surveillance is not always deemed adequate or satisfactory. In contrast to PanINs, which are difficult to identify and monitor clinically, IPMNs represent a unique opportunity to block the progression of pancreatic tumor before an incurable invasive cancer develops. Additional biomarkers to assist with the identification of malignancy (invasive carcinoma or high-grade dysplasia) and in making the surgical decision would be highly desirable. Therefore in Aim 3, using both our newly reported genetically engineered mouse model for IPMN and human samples, we seek to identify protein biomarkers in sera exosomes that can aid in making these difficult clinical decisions and/or impact IPMN growth and progression. The success of the application will magnify our knowledge of an understudied pancreatic precancerous lesion, which hopefully will not only result in better treatment and detection for patients with PDA derived from IPMN, but will also those with PDA associated with PanIN.